Synthesis and pharmacological evaluation of dual acting antioxidant A(2A) adenosine receptor agonists

J Med Chem. 2012 Apr 12;55(7):3521-34. doi: 10.1021/jm300206u. Epub 2012 Mar 29.

Abstract

A series of adenosine-5'-N-alkylcarboxamides and N(6)-(2,2-diphenylethyl)adenosine-5'-N-alkylcarboxamides bearing antioxidant moieties in the 2-position were synthesized from the versatile intermediate, O(6)-(benzotriazol-1-yl)-2-fluoro-2',3'-O-isopropylideneinosine-5'-N-alkylcarboxamide (1). These compounds were evaluated as A(2A) adenosine receptor (A(2A)R) agonists in a cAMP accumulation assay, and a number of potent and selective agonists were identified. Three of these compounds were evaluated further in an ischemic injury cell survival assay and a reactive oxygen species (ROS) production assay whereby 15b and 15c were shown to reduce ROS activity and cell death due to ischemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / chemical synthesis*
  • Adenosine / pharmacology
  • Adenosine A2 Receptor Agonists / chemical synthesis*
  • Adenosine A2 Receptor Agonists / pharmacology
  • Amides / chemical synthesis*
  • Amides / pharmacology
  • Animals
  • Antioxidants / chemical synthesis*
  • Antioxidants / pharmacology
  • CHO Cells
  • Cell Hypoxia
  • Cell Line
  • Cell Survival / drug effects
  • Cricetinae
  • Cricetulus
  • Cyclic AMP / biosynthesis
  • Humans
  • Models, Molecular
  • Myoblasts / cytology
  • Myoblasts / drug effects
  • Myoblasts / metabolism
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Rats
  • Reactive Oxygen Species / metabolism
  • Receptor, Adenosine A2A / metabolism*
  • Reperfusion Injury / pathology
  • Structure-Activity Relationship

Substances

  • Adenosine A2 Receptor Agonists
  • Amides
  • Antioxidants
  • Reactive Oxygen Species
  • Receptor, Adenosine A2A
  • Cyclic AMP
  • Adenosine